Osteoporosis is a leading disease of aging characterized by decreased bone mass and increased fracture risk as a consequence of increased bone resorption by osteoclasts (OCs) and decreased bone formation by osteoblasts (OBs). During aging, increased pro-inflammatory factors mediate low-level chronic inflammation (LLCI) through NF-?B signaling, which promotes bone resorption and also inhibits bone formation. However, the initiating factor(s) and molecular mechanisms linking LLCI to bone loss during aging remain unclear. We have discovered that TRAF3, a member of TNF receptor-associated factor (TRAF) family of proteins , directly limits OC formation by ? , and specific deletion of TRAF3 in OB lineage cells results in age-related osteoporosis accompanied by reduced bone formation and increased bone resorption due to increased RANKL expression by OB lineage cells. RANKL degrades TRAF3 to promote OC formation, and we recently found that TGF?1 degrades TRAF3 in OB precursors to inhibit OB differentiation. Importantly, the bone and marrow of aged mice have reduced TRAF3 levels associated with increased cytokines and chemokines, including RANKL and TGF?1. Furthermore, deletion of TRAF3 in either OB or OC lineage cells in mice results in an early increase in LLCI in their bone marrow with a pattern similar to that of aged mice. These findings directly link TRAF3 to age-associated LLCI and osteoporosis, pointing to critical multiple roles of TRAF3 to maintain bone formation and inhibit LLCI and bone resorption. Thus, stabilization of inhibiting non-canonical NF- B signaling TRAF3 could be a novel strategy to prevent/treat age-related osteoporosis. Inhibitor of apoptosis proteins (IAPs) induce TRAF3 ubiquitin degradation in cells, and we found that the IAP antagonist, SM-164, prevents RANKL- and TGF?1-induced TRAF3 degradation in OC and OB cells, respectively, and importantly, it inhibits OC formation and stimulates OB differentiation in vitro, and short-term intermittent SM-164 significantly increased bone mass in mice. myeloma In addition, TGF?1 induced TRAF3-dependent GSK-3? phosphorylation in OB precursors, leading to degradation of RelB, which also binds to and inhibits RelA activation. The proposed studies will investigate 1) if increased TGF?1 during aging induces IAPs to degrade TRAF3 in OB precursors, resulting in NF-?B activation and LLCI; 2) if TRAF3 degradation leads to RelB degradation via PI3K/AKT mediated-GSK-3? activation, resulting in RelA-mediated LLCI, including increased RANKL and TGF?1 production; and 3) if TRAF3 stabilization by SM-164 prevents age-related and ovariectomy-induced osteoporosis by inhibiting bone resorption and stimulating bone formation. The proposed studies will clarify the mechanisms whereby TRAF3 limits inflammatory cytokine-induced age-related osteoporosis and importantly, will provide proof of principle that inhibition of IAP-induced TRAF3 degradation may be a novel anti- osteoporosis treatment with a dual effect to inhibit resorption and increase bone formation.